We have previously shown in transgenic mice that transforming growth factor (TGF) dramatically enhances c-myc-induced hepatocarcinogenesis by promoting proliferation and survival of hepatocellular carcinoma (HCC) cells. As transgenic livers display increased levels of mature TGF-b1 from the early stages of hepatocarcinogenesis, we have now assessed whether impairment of TGF-b1 signaling contributes to the deregulation of cell cycle progression and apoptosis observed during this process. Focal preneoplastic lesions lacking expression of TGF-b receptor type II (TRbII) were detected in c-myc/TGF but not in c-myc livers. In c-myc/TGF-a mice 40% (2/5) of adenomas and 90% (27/30) of HCCs showed down-regulation of TbRII expression in comparison to 11% (2/18) of adenomas and 47% (14/30) of HCCs in c-myc mice. Down- regulation of the TGF-b1-inducible p15INK4B mRNA and reduced apoptotic rates in TbRII-negative HCCs further indicated the disruption of TGF-b1 signaling. Furthermore, both TbRII- negative and -positive c-myc HCCs, but not c-myc HCCs, were characterized by decreased levels of the cell cycle inhibitor p27. These results suggest: 1) an inverse correlation of decreased p27 expression with the particularly strong expression of TGF-a in these lesions, consistent with the capacity of TGF signaling to post-transcriptionally regulate p27, and 2) the presence of alternative, downstream defects of TGF-b1 signaling in c-myc/TGF-a HCCs that may impair the growth-inhibitory response to TGF-b1. Thus, the accelerated neoplastic development in c-myc/TGF mice is associated with an early and frequent occurrence of TbRII-negative lesions and with reduced levels of p27 in HCC cells, indicating that disruption of TGF- b1 responsiveness may play a crucial role in the enhancement of c-myc- induced hepatocarcinogenesis by TGF-a. - Apoptosis, c-myc, Growth factors, Hepatocarcinogenesis, Liver, Oncogenes, TGF-alpha, TGF-beta, Transgenic Mice, - Neither Human Subjects nor Human Tissues